Abnormal prostate growth is most commonly associated with Benign Prostate Hyperplasia (BPH) or prostate cancer. By age 50, one-third of American men have microscopic signs of prostate cancer, and by age 75, one-half to three-quarters of men's prostates will have cancerous changes. Most of these cancers either remain latent, producing no signs or symptoms, or they are so slow-growing, or indolent, that they never become a serious threat to health. A much smaller number of men will actually be treated for prostate cancer. About 16 percent of American men will be diagnosed with prostate cancer during their lifetime; 8 percent will develop significant symptoms; and 3 percent will die of the disease. The causes of prostate cancer are not well understood.
Risk factors include: 1) Age. In the United States, prostate cancer is found mainly in men over age 55. The average age of patients at the time of diagnosis is 70. 2) Family history of prostate cancer. A man's risk for developing prostate cancer is higher if his father or brother has had the disease. 3) Race. This disease is much more common in African American men than in white men. It is less common in Asian and American Indian men. 4) Diet and dietary factors. Some evidence suggests that a diet high in animal fat may increase the risk of prostate cancer and a diet high in fruits and vegetables may decrease the risk.
Studies are in progress to learn whether men can reduce their risk of prostate cancer by taking certain dietary supplements. Although a few studies suggested that having a vasectomy might increase a man's risk for prostate cancer, most studies do not support this finding. Scientists have studied whether benign prostatic hyperplasia, obesity, lack of exercise, smoking, radiation exposure, or a sexually transmitted virus might increase the risk for prostate cancer. At this time, there is little evidence that these factors contribute to an increased risk.
BPH is the abnormal growth of benign prostate cells. In BPH, the prostate grows larger and presses against the urethra and bladder, interfering with the normal flow of urine. More than 50 percent of the men in the United States between the ages of 60 and 70 and as many as 90 percent between the ages of 70 and 90 have symptoms of BPH. About 50 percent of men with BPH develop symptoms serious enough to warrant treatment.
The prostate normally starts out about the size of a walnut. By the time a man is age 40, the prostate may already have grown to the size of an apricot; by the age of 60, it may be as big as a lemon. BPH is a troublemaker because the prostate, as it enlarges, presses against the bladder and the urethra, blocking the flow of urine. A man with BPH may find it difficult to initiate a urine stream or to maintain more than a dribble. He also may need to urinate frequently, or he may have a sudden, powerful urge to urinate. Many men are forced to get up several times a night; others have an annoying feeling that the bladder is never completely empty. Straining to empty the bladder can make matters worse; the bladder stretches, the bladder wall thickens and loses its elasticity, and the bladder muscles become less efficient. The pool of urine that collects in the bladder can foster urinary tract infections, and trying to force a urine stream can produce backpressure that eventually damages the kidneys.
The kidneys are where urine is formed, as waste products are filtered from the blood. BPH sometimes leads to problems. For instance, a completely blocked urethra is a medical emergency requiring immediate catheterization, a procedure in which a tube called a catheter is inserted through the penis into the bladder to allow urine to escape. Other serious potential complications of BPH include bladder stones and bleeding. BPH cannot be cured, but its symptoms can be relieved by surgery or by drugs in many cases.
Although the popularity of prostate surgery has diminished since drug therapy became available (a total of 250,000 procedures were performed in 1996, down from 400,000 in 1988), operations for BPH remain the most common surgery performed on American men. Several types of surgery can relieve the symptoms of an enlarged prostate. They are: transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP), transurethral needle ablation (TUNA), and open prostatectomy.
TURP accounts for more than 90 percent of all BPH surgeries. The procedure relieves symptoms quickly, typically doubling the urinary flow within weeks. Using either a tiny blade or an electric loop, the surgeon pares away the urethra's lining and bits of excess prostate tissue. Gradually the passageway is expanded. A TURP patient is usually hospitalized for several days after surgery. During convalescence, a catheter remains in the bladder through the penis to drain out urine. About 5 percent of men become partially incontinent after the TURP procedure-although the incontinence sometimes clears up over time. In addition, some men develop scarring in the urethra that can block urination. As many as 10 percent will need repeat surgery because prostate tissue grows back. About 5 percent of men become impotent after the TURP procedure. But TURP does not usually affect a man's ability to have an erection or an orgasm, since the nerves that control erection lie outside the prostate and are not touched by the operation. A more common side effect is a dry, or retrograde, ejaculation. It occurs after surgery when the neck of the bladder fails to close properly during ejaculation. The result is that semen spurts backward into the bladder rather than through the penis. Men who experience this side effect still have the sensation of an orgasm but are unable to father children.
Transurethral incision of the prostate (TUIP) is used on small prostate glands of 30 grams or less and is used far less frequently than TURP. Like TURP, TUIP is performed by passing an instrument through the penis to reach the prostate. The difference is that a doctor makes only one or two small cuts to relieve pressure in the prostate rather than trimming away tissue. Like TURP, the procedure considerably increases the urine flow.
Transurethral needle ablation (TUNA) uses radio frequency energy delivered through needles to kill excess prostate tissue. A catheter that deploys the needles toward the obstructing prostate tissue is inserted into the urethra before the procedure begins. Some clinical studies have reported that TUNA improves the urine flow with minimal side effects when compared with other procedures.
Open prostatectomy is another surgical method for treatment of enlarged prostate. The word “open” refers to the fact that a surgeon makes an incision to reach the prostate, instead of inserting an instrument through the urethra. Open prostatectomy may involve either a radical or a partial procedure. A radical prostatectomy, which removes the whole prostate, is done for cancer. The incision is made through either the lower abdomen or the perineum. Partial prostatectomy, which leaves the posterior portion of the prostate intact, is used to treat BPH. The incision for a partial prostatectomy is usually through the abdomen. Open prostatectomy once was the sole recourse for an enlarged prostate. Today it is used only on extremely large prostates, which represent about 5 percent of all cases.
As an alternative to surgery, drug therapy has been effective in the treatment of BPH. Two major classes of drugs are used: alpha adrenergic blockers and finasteride. Alpha adrenergic blockers were originally used for the treatment of high blood pressure, to relax smooth muscles in blood vessel walls. In BPH, they relax the muscular portion of the prostate and the bladder neck. This allows urine to flow more freely. In the average patient, these drugs increase the rate of urine flow and reduce symptoms, often within days. Side effects include dizziness, fatigue, and headache.
Finasteride shrinks the prostate by blocking an enzyme that converts the male hormone testosterone into a more potent, growth-stimulating form. Some, but not all, studies show that taking finasteride for at least six months can increase urinary flow rate and reduce symptoms. It seems to work best for men who have greatly enlarged prostates. In a small percentage of men, the drug can affect sexual activity, decreasing a man's interest in sex, diminishing his ability to have an erection, and causing problems with ejaculation. It sometimes also causes tenderness or swelling of the breasts. It may cause a drop in PSA levels.
In summary, prostate cancer and BPH are common ailments of aging men with the cost to health care reaching the billions of dollars. The present treatments, though effective in some cases (hormonal/surgical), are mostly palliative in nature and can have considerable side effects (incontinence, impotence, recurrence, high cost). The underlying molecular basis for prostate hypertrophy remains unclear and therefore, the development of tailored therapies that treat the underlying cause cannot be devised.
The Insulin-related gene family is comprised of structurally related proteins with diverged functions. These peptide hormones are known to regulate cell growth, metabolism and several tissue-specific functions. Members of this family include insulin, insulin like growth factors 1 and 2 (IGF I, 11), relaxin, Insulin 3, Insulin 4, Insulin 5, and Insulin 6. The length of the C-peptide as well as presence of additional D and E peptides at the end distinguish proIGFI and II from the rest of the insulin-related family members. These peptide hormones are synthesized as preprohormones comprising of a signal peptide, a B-chain, a connecting C-peptide, and an A-chain. The mature proteins are generated by proteolytic cleavage of the signal and the connecting peptide by prohormone convertases, and the joining of the A- and the B-chains by inter- and intra-disulfide bonds. The spacing of the cysteine residues is conserved, and it is the conserved cysteine motif, the signal peptide, conserved glycine at the end of the B-peptide, and a few conserved hydrophobic residues in the A- and B-peptide that provide a signature for classification of proteins into insulin gene family.
Insulin 6 (Ins16) was identified through the insulin gene family signature motif from the expressed sequence tag (EST) databases by several groups in numerous and varied mammalian species, including mice, rats, and humans (see, e.g. Lok et al., Biol Reprod. 2000 Jun;62(6):1593-9). The deduced coding region of mouse Ins16 is 191 amino acids and the human Ins 16 is 213 amino acids. The difference in the prohormone length between the mouse and the human is due primarily to the slightly longer C-peptide in the humans. The predicted B-domain is 34 amino acids and the A-domain is 38 amino acids, thus making the mature Ins16 peptide 72 amino acids long. The putative B- and A-domains of human are ˜55% identical to mouse Ins16, 43% to human relaxin, 38% to Insulin 3, 36% to human Insulin, 36% to IGFII, 33% to IGFI, 28% to Insulin 5, and 24% to Insulin 4.
Relevant Literature
Relevant literature includes Lok et al., Biol. Reprod. 62 (6), 1593-1599 (2000); U.S. Pat. No. 5,959,075; and S. Y. Hsu, Mol. Endocrinol. 13 (12), 2163-2174 (1999).